Most cancer chemotherapy and radiation therapy kills cancer cells by damaging their DNA and preventing DNA replication. Cancer cells resist therapy and relapse by increasing their ability to repair their DNA and then proceed to replicate their DNA. Identifying the DNA repair proteins that cancer cells use to repair their DNA after therapy would provide new targets to enhance therapy and prevent relapse. Small chemical inhibitors of those target DNA repair and replication proteins could prevent cancer cells from escaping therapy.
We previously demonstrated that Metnase is important for DNA repair. We have now found that is required for DNA replication fork re-start after stalling. Replication forks can stall at sites of cross-linked DNA. We previously generated a class of Metnase and Intnase (also termed Gypsy Integrase, a related protein required for DNA replication) inhibitors that dock into their transpoase domains, which are similar to the retroviral integrase family of proteins. By connecting a potent Metnase inhibitor with a nitrogen mustard DNA alkylating agent we can both create a drug that would be much more difficult for cancer cells to deal with. In one molecule DNA is cross-linked by the nitrogen mustard group, which would stall replication forks, and at the same time, Metnase is inhibited, which is required to re-start stalled replication forks. This would inhibit the very mechanism by which the cell would deal with the cross linked DNA.